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Abstract Objective HIV/HCV co-infection is characterised by accelerated progression of liver disease. Recently, the rsl2979860 C/T polymorphism in the IL28B gene has been linked to progression towards cirrhosis in HCV mono-infected patients and to treatment response of HCV-infection in HIV/HCV co-infected patients. Our aim was to clarify by non-invasive techniques if this polymorphism affects fibrosis progression in HIV/HCV co-infection. Methods In a cross-sectional design, liver stiffness (transient elastography), surrogate markers of liver fibrosis (APRI and FIB-4 scores) and rsl2979860 genotypes were analysed in 84 HCV/H1V co-infected patients. IL28B genotypes were determined by real-time PCR using a light cycler. In 56 HIV/HCV co-infected patients we also studied progression of fibrosis in relation to rsl2979860 C/T genotypes over two years. Results 82% of the patients were on HAART (74% without detectable HI viremia) and 67% were haemophiliacs, respectively. HCV genotype 1 was present in 62%. Cross-sectional median liver stiffness was 7.4 kPa and correlated with APRI and FIB-4 scores (r = 0.6 each, p < 0.001). Frequencies of IL28B genotypes were: CC 50%, CT 43% and TT 7%. In the cross-sectional analysis liver stiffness values were not different between the various IL28B-genotypes. Upon follow-up under HAART carriers of a C allele did not show further progression, while liver stiffness significantly increased in HIV/HCV co-infected patients with the T allele (p = 0.047). Conclusion Although progression of liver fibrosis was low under HAART in our cohort, progression was more pronounced in HIV/HCV genotype 1 co-infected patients with the T allele.

Background & Aims: Toll-like receptor (TLR) 2 and nucleotide-binding oligomerisation domain (NOD) 2 recognize distinct pathogen-associated molecular patterns (PAMS) on the cell surface and in the cytoplasm, respectively. Since they may contribute to susceptibility to spontaneous bacterial peritonitis (SBP), we studied the effects of TLR2 gene variants on susceptibility for SBP in relation to the previously reported NOD2 alleles., Methods: Overall, 150 patients with liver cirrhosis and ascites were genotyped for TLR2 gene variants -16934 (rs4696480), Arg753Gln (rs5743708), Pro631His (rs5743704) and the TLR2 GT microsatellite polymorphism in intron 2. Patients were monitored for SBP over two years. TLR2 SNPs were identified by hybridization probe assays on a LightCycler system. Numbers of GT repeats were determined with an ABI310 sequencer and Genescan Analysis 2.1 software., Results: Fifty two patients (35%) had SBP. Unlike the TLR2 Arg753Gln and Pro631His mutations, SBP was significantly more frequent in patients with the TLR2 -16934 TT genotype (38.5% vs. 15.3%; p = 0.002) and in carriers with two long tandem GT repeat alleles (>20) (53.8% vs. 25.5%; p = 0.001). A multivariate analysis confirmed TLR2 GT microsatellite polymorphism (OR = 3.8, p = 0.002) and NOD2 variants (OR = 3.3, p = 0.011) as independent predictors of SBP, and the simultaneous presence of both risk factors indicated a particularly high risk for SBP (OR = 11.3, p = 0.00002)., Conclusions: Analogous to NOD2 risk variants, TLR2 polymorphisms indicate increased susceptibility toward SBP in cirrhotic patients with ascites, and the combination of the TLR2 GT microsatellite polymorphism with at least one NOD2 risk variant enables improved identification of patients with a high risk for SBP., (Copyright © 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Objective: To determine the long-term antiretroviral efficacy and tolerability of dual protease inhibitor (PI) therapy with indinavir (IDV)/ritonavir (RTV) at 400/400 mg twice a day (BID) in combination with two nucleoside reverse trancriptase inhibitors (NRTIs)., Design and Methods: In an open-label, uncontrolled multicentre clinical trial, antiretroviral therapy naive patients (n = 93) with a high median baseline HIV-1 RNA level of 210 000 copies/mL (range 17 000-2 943 000) and a median CD4 cell count of 195 copies/microL (range 4-656 copies/microL) were started on a regimen of either zidovudine (ZDV)/lamivudine (3TC) (49%), stavudine (d4T)/3TC (38%) or d4T/didanosine (ddI) (14%) plus RTV and IDV, each at 400 mg BID. CD4 cell counts and HIV RNA were determined at 4-week intervals for a duration of 72 weeks. Statistical analysis was performed on treatment as well as by intent to treat, where missing values were counted as failures., Results: HIV RNA levels below the limit of detection were achieved in 59.5% (< 80 copies/mL) and 63% (< 500 copies/mL) of patients according to the intent to treat analysis at week 72. In the on treatment analysis, the proportion of patients reaching an undetectable viral load was 94.5% (< 80 copies/mL) and 100% (< 500 copies/mL), respectively. Apart from diarrhoea and nausea, serum lipid abnormalities were identified as the most prominent adverse reaction. No cases of nephrotoxicity occurred during the entire observation period of 72 weeks., Conclusions: Our results demonstrate that quadruple therapy with RTV/IDV and two NRTIs induces potent, durable and safe HIV suppression and might be particularly beneficial as a first line therapy for patients with a high baseline viral load.

Objectives: The impact of intrahepatic messenger RNA (mRNA) levels of interferon gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) on the outcome of antiviral treatment of chronic hepatitis C was evaluated., Methods: Semiquantitative mRNA determination was performed on 36 pretreatment liver biopsies by reverse transcription/competitive polymerase chain reaction., Results: Sustained response (normal aminotransferase levels and negative hepatitis C virus [HCV] RNA for more than 6 months) was achieved in 13 patients, whereas 23 of 36 patients did not achieve sustained response (12 partial responders, 11 complete nonresponders). In sustained responders, pretreatment intrahepatic mRNA levels of IFN-gamma and TNF-alpha were lower than in nonsustained responders (IFN-gamma, 0.23 +/- 0.10 vs. 0.35 +/- 0.07, respectively; p = 0.024 and TNF-alpha, 1.2 +/- 0.7 vs. 2.3 +/- 1.4, respectively; p= 0.009); similarly, HCV viral load was lower in sustained responders than in nonresponders (663,424 +/- 756,389 copies/mL vs. 1,656,713 +/- 1,517,683 copies/mL, respectively; p = 0.037). In addition, TNF-alpha mRNA levels were correlated to HCV viral load and liver fibrosis scores., Conclusions: Higher intrahepatic mRNA levels of IFN-gamma and TNF-alpha may reflect interferon resistance of HCV strains and may contribute to tissue damage in patients refractory to antiviral treatment.